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Diabetic Nephropathy; Causes, Symptoms, Treatment

Diabetic Nephropathy (DN) or diabetic kidney disease is a syndrome characterized by the presence of pathological quantities of urine albumin excretion, diabetic glomerular lesions, and loss of glomerular filtration rate (GFR) in diabetics. Diabetes may be classified as type 1 (autoimmune β-cell destruction and absolute insulin deficiency), type 2 (relative insulin deficiency and resistance), and other types (eg, pancreatic disease).

Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 hr, or 300 mg/g creatinine), a progressive decline in glomerular filtration rate (GFR), arterial hypertension, and increased cardiovascular morbidity and mortality.

Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months or years.^[rx]^[rx] Early on there are typically no symptoms.^[rx] Later, leg swelling, feeling tired, vomiting, loss of appetite, or confusion may develop. Complications may include heart disease, high blood pressure, bone disease, or anemia.^[rx]^[rx]

Pathophysiology of Diabetic Nephropathy

DN is a clinical syndrome characterised by the insistent albuminuria that should be confirmed on at least two occasions separated by 3-6 months, by continuous decline in the glomerular filtration rate (GFR), and by increased arterial blood pressure. DN is characterised by different events. The characteristic occurrence is thickening of the glomerular basement membrane (GBM). After renal damage, the thickening of the basement membrane starts, which leads to pathologic modifications in mesangial and vascular cells. It includes formation of AGEs, accumulation of polyols, and activation of protein kinase C [rx,rx]. It leads to activation of the inflammatory pathway playing a significant role in the damage of GBM [rx].

Secondly, the renal hemodynamic anomaly is similar in both types of diabetes [rx]. An initial physiologic abnormality is glomerular hyper-filtration related to intra-glomerular hypertension [rx]. This is complemented by the onset of microalbuminuria. Microalbuminuria is considered the first sign indicating the onset of DN [rx].

The exact pattern observed in the pathophysiology of DN is:

Hyperglycaemia
Thickening of GBM
Glomerular hyper-filtration
Impaired endothelial integrity
Onset of microalbuminuria
Impairment of nitric oxide transport
Loss of afferent/efferent auto-regulatory control
Continued loss of glomerular filtration capabilities

Causes of Diabetic Nephropathy

Hyperglycemia – Hyperglycemia is a significant risk factor for the development of microalbuminuria, both in type 1 and in type 2 DM [rx,rx,rx]. A reduction of 1% in HbA1c is associated with a 37% decrease in microvascular endpoints [57]. In the presence of micro- and macroalbuminuria the role of metabolic control is less defined, even though some studies showed a deleterious effect of high glucose levels on GFR [rx,rx].
Arterial Hypertension – Arterial hypertension is a main risk factor for the development of DN [rx,rx], and probably the best known relevant factor related to its progression. Analysis of UKPDS showed that every 10 mmHg reduction in systolic BP is associated with a 13% reduction in the risk of microvascular complications, with the smallest risk among those patients with systolic BP <120 mm Hg [rx].
Smoking – Smoking is a risk factor for DN [rx,rx] and might contribute to its progression [rx]. Although some studies did not confirm these observations [rx,rx], it is strongly recommended to quit smoking in any phase of DN, also aiming to reduce the associated cardiovascular and cancer risk.
Dyslipidemia – In type 2 DM, elevated serum cholesterol is a risk factor for the development of DN [rx,rx]. In type 1 DM patients increased serum triglycerides, total and LDL-cholesterol were associated with micro- and macroalbuminuria [rx,rx]. High serum cholesterol also seems to be a risk factor for GFR loss in macroalbuminuric type 1 diabetic subjects [rx].
Proteinuria – Proteinuria itself could lead to progression of DN. Proteinuria >2 g/24 h is associated with a greater risk of ESRD [rx]. Increased leakage of albumin may induce glomerular damage probably through activation of inflammatory cascades [rx]. This would be a reason to target decreased urinary albumin excretion in DN treatment.
Glomerular hyperfiltration – Elevated GFR values are present in about one third of type 2 DM patients [rx,rx] and theoretically it could cause DN due to glomerular damage [rx]. Studies led to controversial findings regarding its role as a risk factor for the development of DN [rx,rx]. Type 2 DM patients with a single-kidney more often present increased UAE levels [rx,rx]. On the other hand, type 1 DM patients with only one kidney do not have a more aggressive disease [rx]. Glomerular hyperfiltration probably plays a small role, if any, in the development of DN [rx].
Dietary factors – Increased dietary protein intake seems to be associated with the presence of higher UAE values, at least in patients with type 1 DM [rx]. In patients with type 2 DM this association has not been documented. The source of proteins in the diet also seems to be related to the presence of DN. A higher intake of fish protein is related to a lower risk of microalbuminuria in type 1 DM patients [rx]. The mechanisms involved in these findings are unknown but probably related to hemodynamic factors [rx].
Vascular disease – includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome, and vasculitis.
Glomerular disease – comprises a diverse group and is classified into:
- Primary glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
- Secondary glomerular disease such as diabetic nephropathy and lupus nephritis

Congenital disease such as polycystic kidney disease.
Tubulointerstitial disease – includes drug- and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy.
Obstructive nephropathy – is exemplified by bilateral kidney stones and diseases of the prostate such as benign prostatic hyperplasia.
On rare cases – pinworms infecting the kidney can also cause nephropathy.
Nontraditional causes of CKD (CKDu) – are denoted if the common causes of CKD are not present:
- CKD of unknown cause is the subject of study by the Sri Lanka Ministry of Health and the World Health Organization 2009–2012.^[rx]
- Mesoamerican nephropathy, a form of CKDu, is “a new form of kidney disease that could be called agricultural nephropathy”.^[rx]
Autoimmune disease, such as lupus erythematosus
Infection with hepatitis B, hepatitis C or syphilis
Certain medications, such as gold salts and nonsteroidal anti-inflammatory drugs
Solid cancerous tumors or blood cancers

Symptoms of Diabetic Nephropathy

CKD is initially without specific symptoms and is generally only detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases:

Blood pressure – is increased due to fluid overload and production of vasoactive hormones created by the kidney via the renin–angiotensin system, increasing one’s risk of developing hypertension and/or suffering from congestive heart failure.
Urea accumulates – leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Due to its high systemic circulation, urea is excreted in eccrine sweat at high concentrations and crystallizes on skin as the sweat evaporates (“uremic frost”).
Potassium accumulates – in the blood (hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the glomerular filtration rate falls to less than 20–25 ml/min/1.73 m², at which point the kidneys have decreased ability to excrete potassium.^[rx]
Erythropoietin synthesis is decreased causing anemia.
Fluid volume overload – symptoms may range from mild edema to life-threatening pulmonary edema.
Hyperphosphatemia – due to reduced phosphate excretion, follows the decrease in glomerular filtration. Hyperphosphatemia is associated with increased cardiovascular risk, being a direct stimulus to vascular calcification.^[rx] Moreover, circulating concentrations of fibroblast growth factor-23 (FGF-23) increase progressively as the renal capacity for phosphate excretion declines, but this adaptative response may also contribute to left ventricular hypertrophy and increased mortality in CKD patients.^[rx]^[rx]
Hypocalcemia – due to 1,25 dihydroxyvitamin D₃ deficiency (caused by stimulation of FGF-23 and reduction of renal mass),^[rx] and resistance to the calcemic action of parathyroid hormone.^[rx] Osteocytes are responsible for the increased production of FGF-23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D₃).^[rx] Later, this progresses to secondary hyperparathyroidism, renal osteodystrophy, and vascular calcification that further impairs cardiac function. An extreme consequence is the occurrence of the rare condition named calciphylaxis.^[rx]
The concept of chronic kidney disease-mineral bone disorder (CKD-MBD)– ^[rx]^[rx] currently describes a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of: (1) abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, or vitamin D metabolism; (2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength (renal osteodystrophy); and( 3) vascular or other soft-tissue calcification.^[rx] CKD-MBD has been associated to poor hard outcomes.^[rx]
Metabolic acidosis – (due to accumulation of sulfates, phosphates, uric acid etc.) may cause altered enzyme activity by excess acid acting on enzymes; and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia).^[rx] Acidosis is also due to decreased capacity to generate enough ammonia from the cells of the proximal tubule.^[rx]
Iron deficiency anemia – which increases in prevalence as kidney function decreases, is especially prevalent in those requiring haemodialysis. It is multifactoral in cause, but includes increased inflammation, reduction in erythropoietin, and hyperuricemia leading to bone marrow suppression.
People with CKD – suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with CKD and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.^[rx]
Sexual dysfunction – is very common in both men and women with CKD. A majority of men have a reduced sex drive, difficulty obtaining an erection, and reaching orgasm, and the problems get worse with age. A majority of women have trouble with sexual arousal, and painful menstruation and problems with performing and enjoying sex are common.^[rx]
A usual first symptom – is frequent urination at night: nocturia. Other symptoms include tiredness, headaches, a general feeling of illness, nausea, vomiting, frequent daytime urination, lack of appetite, itchy skin, and leg swelling.^[rx]
swollen ankles, feet, lower legs, or hands caused by water retention
darker urine, due to blood in the urine
shortness of breath
fatigue, caused by lack of oxygen in the blood
nausea or vomiting
metallic taste
Weight gain
Fatigue
Poor appetite
Urine that looks foamy
High cholesterol
Increased protein in the urine (proteinuria)
Decreased protein in the blood, particularly albumin

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Natural clinical course of diabetic kidney disease

The natural history of DN is divided into five stages [rx]

Stage 1 – Renal pathology develops at the onset of diabetes. The growth of the kidney increases by several centimetres. By the time of diagnosis, the GFR and urinary albumin excretion (UAE) have been increased. It can be controlled at this level by onset of insulin.
Stage 2 – The second phase typically lasts for 5-15 years after diagnosis of diabetes. The characteristics of the second phase include: (1)GFR remains elevated due to hyperfiltration. (2)Kidneys remain hypertrophied and UAE rate stays normal.

Stage 3 – The characteristics of stage three are:

Microalbuminuria is present. It occurs in 30-50% of patients after diabetes onset, 80% of whom go on to develop overt nephropathy over 10-15 years.
GFR remains elevated or returns to normal range
Blood pressure starts to rise in 60% of patients

Histological changes-progression is as seen in stage two.

Stage 4 – This stage is also known as clinical nephropathy or overt nephropathy. The characteristic histological features of stage four are formation of the Kimmelstiel-Wilson nodule (focal glomerular sclerosis) and macroproteinuria. It can progress to nephrotic in 30% of patients or may decline in 80% depending on deterioration of GFR.
Stage 5 – As the GFR continues to decline, ESRD may develop. DN is considered the most common cause of ESRD because of associated autoimmune neuropathy and cardiac disease.

The stages of chronic kidney disease (CKD) are mainly based on measured or estimated GFR. There are five stages but kidney function is normal in stage 1 and minimally reduced in stage 2.

Categories of Diabetic Nephropathy

Category C I: Normal or near normal renal structure

These patients (35% of MA and 15% of proteinuria) had normal renal biopsies or showed very mild glomerular, tubular, interstitial and/or vascular changes.

Category C II: Typical diabetic nephropathology

These patients (30% of MA and 50% of proteinuria) had established diabetic lesions with an approximately balanced severity of glomerular, tubulo-interstitial and arteriolar changes, a picture typical of that seen in most T1DM patients with obvious light microscopic DN changes.

Category C III: Atypical patterns of renal injury

These patients (35% of MA and proteinuria) had relatively mild diabetic glomerular changes considering disproportionately severe: (a) Tubular atrophy, TBM thickening and reduplication and interstitial fibrosis (tubulo-interstitial lesions). (b) Advanced glomerular arteriolar hyalinosis commonly associated with atherosclerosis of larger vessels. (c) Global glomerular sclerosis. In C III group these patterns were present in all possible combinations.

Diagnosis of Diabetic Nephropathy

1)Enough time: At least 10 years past the onset of diabetes, but this criterion is often not verifiable in type 2.
2)Persistent albuminuria more than 300 mg in 24 hours
3)Diabetic retinopathy at the same time: Given that almost all patients with type 1 diabetes with diabetic nephropathy have retinopathy, retinopathy in patients with first and second criteria, prove the diagnosis, and lack of it virtually excluded diagnosis.

Renal disease less than 5 years or after 30 years of diabetes onset

Puria, RBC or WBC cast
Serum creatinine test
Microscopic examination of urine
Progressive proteinuria
Progressive renal failure
Acute nephrotic syndrome
Acute renal failure
Macroscopic hematuria

Diagnosis is based on the measurement of abnormal levels of urinary albumin in a diabetic^[rx] coupled with exclusion of other causes of albuminuria. Albumin measurements are defined as follows:^[rx]

Normal albuminuria – urinary albumin excretion <30 mg/24h;
Microalbuminuria – urinary albumin excretion in the range of 30–299 mg/24h;
Macroalbuminuria – urinary albumin excretion ≥300 mg/24h.

Incipient nephropathy is the initial presence of low but abnormal amounts of urine albumin, referred to as microalbuminuria (persistent albuminuria at level 30–299 mg/24 hours). Overt nephropathy or macroalbuminuria (persistent albuminuria at level ≥300 mg/24 hours) develops after many years in type 1 diabetes but may be present at the time of diagnosis of type 2 diabetes.

Screening for DN

Most guidelines recommend screening with a spot urine albumin/creatinine ratio (ACR; normal >30 mg/g creatinine), from either first morning (preferred) or random specimens. An abnormal result is repeated once or twice over a few months for consistency.

Renal biopsy

The routine use of renal biopsy to confirm DN is much debated. Many nephrologists do not biopsy patients with classic features such as retinopathy, duration of diabetes <10 years, slow decline in GFR, gradual progression of proteinuria, and lack of active urinary sediment

Biomarkers

There are limitations in using albuminuria as a marker of DN as many patients experience GFR loss without deterioration in albuminuria and even normoalbuminuria.[rx] In fact, histologically proven advanced diabetic glomerular lesions can develop despite normoalbuminuria.[rx] Furthermore, low-grade albuminuria is a lesser predictor of disease progression than macroalbuminuria.[rx]

Investigations for DN

Urine culture – Exclude infection

Urine microscopy – Examine for red cell cast in glomerulonephritis

Anti-DNA antibodies

Complement level – Exclusion of autoimmune disease

Rheumatoid factor

Igs; Protein electrophoretic strip – Exclude multiple myeloma

Renal ultrasound – Exclude obstructive renal disease, Assess renal anatomy and size

According to NICE guidelines, the following patients should be referred early to the specialist [rx]:

1) Stage 4 and 5 CKD (with or without diabetes)
2) Proteinuria together with hematuria
3) Rapidly declining GFR
4) Hypertension that remains poorly controlled despite use of at least four antihypertensive drugs at therapeutic doses
5) People with, or suspected of having, rare or genetic causes of CKD.

Cytokines

A series of circulating markers of inflammation such as C reactive protein and interleukin 1, 6 and 18, and tumor necrosis factor are increased in DN and their levels correlate with albuminuria and progression to ESRD. In addition, hyperglycemia, TGF-β1 and angiotensin II stimulate the secretion of VEGF, causing the production of endothelial nitric oxide, vasodilation and glomerular hyperfiltration [rx].

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Treatment of Diabetic Nephropathy

Treatment of diabetic nephropathy is based on some principle:

1)Tight control of hyperglycemia
2)control of blood and glomerular pressure
3)Control of dyslipidemia
4)Restriction of protein intake
5)Smoking withdrawal.

However, there are some clinical features that help in making the decision to do renal biopsy, summarised as:

1) Short-duration type 1 diabetes
2) Autoimmune disease
3) Mild or absent retinopathy
4) Red cell casts in urine
5) Significant and persistent proteinuria

Optimal blood glucose control

Control of blood pressure at 120/70 mmHg
Avoidance of potential use of nephrotoxic drugs such as nonsteroidal Antiinflammatory Drugs (NSAIDs), aminoglycosides, etc.
Early detection and management of diabetes, especially in setting of family history.

Potential New Therapies

There is a lot of research ongoing regarding the treatment of DN

High doses of thiamine and its derivative benfotiamine have been shown to reduce the rate of microalbuminuria in experimental diabetes nephropathy, probably due to the decrease in activation of protein kinase C, protein glycation and oxidative stress [rx].
Treatment with a protein kinase C beta inhibitor normalises GFR, decreases albumin excretion rate, and ameliorates glomerular lesions in diabetic rodents [rx].
Pimagedine, a second-generation inhibitor of advanced glycation end product, reduced urinary protein excretion and the decline in GFR in proteinuric type 1 diabetic patients in a randomized, placebo-controlled study [rx].

New therapeutic agents in diabetic nephropathy beyond conventional RAAS inhibition

Glucose-dependent pathway
AGEs reduction: aminoguanidine, pyridoxamine
PPAR agonists: fenofibrate, thiazolidinediones
Incretins: GLP-1 receptor, DPP-4 inhibitor
SGLT2 inhibitor: canagliflozin, dapagliflozin
AMPK activator: AICAR, adiponectin, statins
Vasoactive-pathway
RAAS system: aliskiren, HRP, spironolactone, eplerenone
Endothelial antagonism: avosentan, atrasentan
Intracellular signaling
PKC-β inhibition: ruboxistaurin
Rho kinase inhibitors: fasudil
Prosclerotic GFs inhibition
Anti-PDGF, anti-TGF-β, anti-CTGF, pirfenidone
Anti-inflammatory pathway
Adenosine, pentoxifylline (TNF-α inhibition), adiponectin, statins, mTOR inhibitor
Anti-oxidative pathway
Bardoxolone methyl, N-acetylcysteine, probucol
Glycosaminoglycan, sulodexide, paricalcition.

Summary of novel agents

Category	Mechanism of action	Drug(s)	Human data
Direct renin inhibitors	Blocks conversion of angiotensinogen to angiotensin I.	Aliskiren	RCT
Endothelin inhibitors	Predominantly blocks ET_A receptors on vascular endothelium.	Atrasentan Avosentan	RCT RCT
Vasopeptidase inhibitors	Blocks ACE and neutral endopeptidase. Palosuran blocks urotensin II receptor.	Palosuran Omapatrilat Ilepatril	RCT None None
PKC inhibitors	Blocks PKC-β intracellular signaling.	Ruboxistaurin	RCT, pooled
Aldose reductase	Reduces sorbitol formation by the polyol pathway.	Epalrestat Ponalrestat Tolrestat	Non-RCT Non-RCT None
Phosphodiesterase inhibitors	Increases cellular cAMP with broad effects. Cilostazol blocks PDE3, pentoxifylline is nonspecific and also blocks the adenosine receptor.	Cilostazol Pentoxifylline	RCT RCT, MetaAx
AGE inhibitors	Blocks AGE formation, enhances breakdown, or breaks crosslinks.	Aminoguanidine Pyridoxamine Alegebrium	RCT RCT None
Antioxidative stress	Activation of nuclear transcription factor Nrf2.	Bardoxolone	RCT
Glycosaminoglycans	Reduces heparan sulfate degradation in GBM, anti-inflammatory actions.	Sulodexide	RCT
Antifibrosis	Reduces TGF-β signaling and TNF-α levels but exact mechanism unclear.	Pirfenidone	RCT

Abbreviations: AGE, advanced glycation end-products; cAMP, cyclic adenosine monophosphate; RCT, randomized controlled trial; MetaAx, meta-analysis; GBM, glomerular basement membrane.

Angiotensin receptor blocker (ARB) – In the IDNT trial, 1,715 hypertensive type 2 diabetics with nephropathy were randomly assigned to receive irbesartan, amlodipine, or placebo.[rx] Irbesartan reduced the risk of ESRD or doubling of serum creatinine by 20%–23% compared to amlodipine or placebo.
ACE inhibitor versus ARB – In the DETAIL trial, 250 type 2 diabetics with early DN were randomly assigned to enalapril or telmisartan. Combination therapy with ACEI and ARB compared with ACEI or ARB monotherapy was shown to reduce proteinuria in patients with type 1 and type 2 diabetes [rx, rx]. However, the antiproteinuric effects of combination therapy do not seem to be sufficient for the prevention of renal disease progression or death.
ACE inhibitor and ARB – Earlier studies of combination ACE inhibitor and ARB reported superiority of combination therapy for lowering albuminuria and blood pressure versus either alone, in both type 1 and 2 diabetics.[rx–rx]. ACE inhibition cannot completely inhibit the production of angiotensin II but ARBs can fully inhibit the effect of angiotensin I on AT₁ and this causes the accumulation of angiotensin II that via AT₂ receptor causes dilation of blood vessels and decreased cell proliferation [rx].
Abundant experimental data indicate that thiazolidinediones (TZD) – a family of anti-diabetic drugs that activate the transcription factor peroxisome proliferator activator receptor gamma (PPAR-γ), have direct renoprotective effects [rx–rx]. These effects are most probably exerted by preventing diabetes-induced renal inflammatory processes. However, clinical studies have reported controversial outcomes, with some of them reporting significant antiproteinuric effects [rx–rx], and others demonstrating insignificant effects [rx]
Glitazones – represented by rosiglitazone and pioglitazone, act through the PPR gamma system and are insulin sensitizer drugs that increase the muscle uptake of glucose and diminish the atherogenic profile of the DM patient, and could be used in renal failure [rx,rx]. Rosiglitazone has been shown to decrease UAE in type 2 diabetic patients as compared to glyburide, suggesting a beneficial effect in the prevention of renal complications of type 2 DM [rx].

Treatment of hyperglycemia in the patient with type 2 diabetes mellitus and chronic kidney disease

				Stage of Renal Disease

	Clearance	Reduction of HbA1c	Risk of hypoglycemia	III	IV	V
Glibenclamide [rx,rx]	Hepatic metabolism: 100%. Excretion: bile and feces 50% and urine 50%	-1.5%	High (active metabolites)	Avoid	Avoid	Avoid
Glipizide [rx]	Excretion: metabolites 90% in urine and feces. 10% excreted without metabolization	-1.5%	Low	Can be used	Can be used	Can be used (adjustments)
Glimepyride	Hepatic metabolism 100%. Excretion: urine 60% and feces 40%	-1.5%	Low	Can be used	Can be used	Use with care
Repaglinide [rx,rx]	Hepatic metabolism: 100%. Excretion: 10% urine and 90% feces	-1.0%	Low	Can be used	Can be used	Use with care. Adjust dose
Nateglinide [rx,rx]	Hepatic metabolism: 85%. Excretion: urine 83% and feces 10%. 15% excreted inactive in urine	-0.7%	High (active metabolites)	Use with care	Use with care	Avoid if possible
Acarbose* [rx,rx]	Excretion: urine 34%, feces 51% and <2% in urine in the free or active metabolic form	-0.6%	Low	Can be used	Can be used	Avoid
Rosiglitazone [rx]	Hepatic metabolism and excretion in the urine, of rather inactive metabolites in the urine 64% and feces 23%	-0.6 to 1.5%	Low	Can be used	Can be used	Can be used
Pioglitazone [rx]	Hepatic metabolism and excretion in urine of rather inactive metabolites in the urine 15% and feces 85%	-0.6 to 1.5%	Low	Can be used	Can be used	Can be used
Sitaglipitine [rx,rx]	Excretion: urine 87% and feces 13%, in an unaltered form.	-0.7%	Low	Can be used	Can be used. Reduce dose 50%	Can be used. Reduce dose 75%
Vildagliptine	Excretion: urine: 85% and feces 15%.	-0.7%	Low	Can be used	Can be used	Not recommended
Exanetide [rx]	Metabolism and renal excretion	-1.0%**	Low	Can be used	Not recommended	Not recommended

Renin inhibitors – Renin catalyses the rate-limiting step in the production of angiotensin II. In diabetic rats, aliskiren reduced albuminuria and glomerulosclerosis, and was more effective than perindopril in reducing interstitial fibrosis.[rx]
Repaglinide and nateglinide – [rx] have a short duration of action, are excreted independently of renal function and have a safety profile in patients with renal impairment. These drugs, like the sulfonylureas, are insulin secretagogues, but they act in different cellular membrane channels, and this brings some pharmacological properties such as quick initial action, non-prolonged action and greater effect on post-prandial glycemia.
Endothelin inhibitors – In diabetic rats, an ET_A receptor blockade with atrasentan or avosentan reduced albuminuria and renal fibrosis.[rx,rx] The ASCEND trial of 1,392 type 2 diabetics with overt nephropathy examined the effect of avosentan on time to doubling of serum creatinine, ESRD, or death. Avosentan halved proteinuria but increased fluid retention, edema, and congestive heart failure, resulting in the trial being stopped early
Urotensin and vasopeptidase inhibitors – Vasopeptidase inhibitors can block ACE and neutral endopeptidase. Palosuran is a competitive antagonist of the urotensin II receptor. In diabetic patients with macroalbuminuria, a 2-week course of palosuran in addition to RAS inhibitors reduced albuminuria by 24%.[rx]
PKC inhibitors – Ruboxistaurin is a selective inhibitor of PKC-β. Animal studies with ruboxistaurin showed beneficial effects on reducing mesangial expansion, hyperfiltration, albuminuria, macrophage accumulation, and tubulointerstitial injury.[rx,rx]
Aldose reductase inhibitors – These inhibitors suppress sorbitol accumulation in tissues. Epalrestat reduced mesangial expansion and preserved renal function in diabetic rats.[rx] Another inhibitor – tolrestat – prevented glomerular hypertrophy and hyperfiltration, mesangial cell hypocontractility, and albuminuria in diabetic rats.[rx]
Phosphodiesterase inhibitors – Cilostazol inhibits phosphodiesterase III and reduces thrombospondin-1 and TGF-β expression, attenuating hyperfiltration, albuminuria, and extracellular matrix deposition in diabetic rats.[rx,rx]
Agents targeting oxidative stress – Cellular and mitochondrial ROS formation is an important contributor to the pathophysiology of DN. Targeted inhibitors of ROS generation are emerging but most have not progressed to clinical trials.
Glycosaminoglycans – Sulodexide is a mixture of 80% heparan sulfate and 20% dermatan sulfate. Sulodexide may reduce the enhanced heparan sulfate degradation in the glomerular basement membrane that occurs in DN. It has anti-inflammatory properties and inhibits the hyperglycemia-induced production of ROS, MCP-1, and IL-6 in endothelial cells.[rx]
Antifibrotic agents – Pirfenidone inhibits TGF-β production and TNF-α production in models of DN and non-DN kidney disease. The exact mechanism of action is unclear. In db/db mice with type 2 diabetes, pirfenidone reduced mesangial matrix expansion but did not affect albuminuria.[rx]
Dihydropyridine calcium channel blockers – such as amlodipine and nifedipine, may be worse proteinuria and may progress nephropathy in diabetic and non-diabetic patients. Conversely, non-dihydropyridine calcium blockers such as verapamil and diltiazem, reduce the risk of overt nephropathy and improve size selectivity in glomeruli in diabetic nephropathy
Anti-proteinuric effects of renin-angiotensin-aldosterone system inhibitors – is exacerbated with reducing sodium intake and taking other antihypertensive medications at the same time including diuretics and non-dihydropyridine calcium channel blockers.
Potential benefits of spironolactone as antagonist of aldosterone receptors – was tested in a double-blind study on 59 patients with diabetes 2 that were ever treated with ACEIs or ARBs. Spironolactone 50 mg a day were given in treatment group and another group were given placebo. Urine albumin to creatinine ratio up to 40% and systolic blood pressure 7 mmHg and diastolic blood pressure 3 mmHg were reduce in spironolactone group, whereas these parameters did not change in the placebo group [rx].
Pentoxifylline – is a non-specific phosphodiesterase inhibitor with anti-inflammatory properties; it has been used in patients with peripheral artery disease and alcoholic hepatitis. Several small studies including patients with diabetic nephropathy showed that pentoxifylline had antiproteinuric effects and reduced the rate of decline in eGFR [rx–rx]. Additional data are needed before pentoxifylline can be recommended as treatment for diabetic nephropathy.
Pirfenidone – is an oral synthetic antifibrotic agent that has demonstrated benefits in animal models of diabetic nephropathy and in patients with this syndrome by preventing the progression of renal impairment. Pirfenidone is thus a promising agent for the treatment of diabetic nephropathy, and should be further investigated and advanced [rx, rx].
Endothelin-1 (ET-1) – is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two receptor subtypes, namely ET(A) and ET(B). ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla, whereas activation of ET(A) receptors causes vasoconstriction, mesangial-cell proliferation, extracellular matrix production, and inflammation [rx]
Phosphate binder sevelamer carbonate – a currently used phosphate binder, was shown to significantly reduce HbA1c, fibroblast growth factor 23, and lipids, and to exhibit anti-inflammatory and antioxidant properties, independently of phosphate level reduction in patients with diabetes and early kidney disease [rx]. However, a recent trial did not show any benefits of sevelamer regarding reductions in HbA1c or albuminuria overall in patients with type 2 diabetes and diabetic nephropathy, except for very specific groups of patients [rx].
Bardoxolone methyl – is an oral antioxidant. Its structure and activity profile is similar to cyclopentenone prostaglandins that exert anti-inflammatory effects by inhibiting the nuclear factor κB pathway. Experimental data of drug-induced or ischemic acute kidney injury have shown beneficial effects [rx]. According to this trial, bardoxolone methyl therapy significantly increased estimated glomerular filtration rate (eGFR) at 1 year of follow-up, while placebo therapy did not have any effects on the eGFR [rx].
Aliskiren – an oral direct renin inhibitor, has a similar degree of blood pressure-lowering properties as other agents. In the AVOID trial, aliskiren combined with losartan was associated with a significantly greater reduction in proteinuria, but no significantly greater antihypertensive effect, than losartan monotherapy [rx]
Vitamin D therapy – has recently received attention as a potential treatment option in DN. Initial mouse studies showed that mice unable to make vitamin D or lacking vitamin D receptors had an increase in RAAS activity and even exhibited significant proteinuria.^[rx]
Gene and cell-based therapy – Gene therapy involves introducing a gene into cells to increase the production of a protein of interest. A carrier or vector such as modified adenovirus is employed to deliver the gene to the nucleus where the protein coded by the gene is produced by the cellular machinery. Gene therapy targeting TGF-β/SMAD signaling has shown promise in reducing kidney injury in diabetic models. Ka et al studied Smad7 gene therapy in the db/db mouse model of type 2 diabetes. Treatment inhibited TGF-β/SMAD and NF-κB activation, resulting in a reduction in proteinuria, macrophage infiltration, inflammation, podocyte injury, and renal fibrosis.[rx]
Dyslipidemia – The most common lipid disorder in diabetes is increased triglycerides and reduced HDL. Although LDL levels in these patients is usually normal, but it has high atherogenic properties. Accompaniment of glucose intolerance or diabetes, high blood pressure, low HDL and high triglycerides, obesity and sometimes high LDL are known as metabolic syndrome, will lead to increased risk of cardiovascular disease. Therapeutic purposes by the American diabetes association are: The blood triglyceride level of less than 150 mg/dL, HDL over 60 mg/dl and LDL less than 100 mg/dL.
Protein restriction – High protein intake can increase glomerular filtration and sclerosis. Studies have shown that reducing protein intake in diabetic patients can reduce proteinuria and slow the progression of renal failure. Protein restriction can lead to decrease symptoms of uremia and delay need for dialysis. The possible mechanism of effect of protein restriction is reduced hyperfiltration in healthy nephron.